The Human Genome Project was funded and pursued based on the premise that the sequencing of the human genome would reveal the genetic basis for complex diseases that have a strong inheritable component, including cardiovascular disease, neurodegenerative conditions, and metabolic diseases such as diabetes. It was believed that this information would lead to new drug targets for these widespread diseases. However, thousands of genome-wide association studies (GWAS) have shown that the genetic variation associated with these complex diseases does not occur within genes, but rather in intergenic regulatory regions that control the levels of particular genes. Similarly, approximately 20% of Mendelian disorders do not have a detectable coding mutation, suggesting that the causal mutation is in a gene regulatory element. It is very difficult to assign functional roles to these regulatory elements as they often are located in distant locations from their target genes.
The human genome encodes approximately 50,000 genes. Understanding how those genes are regulated and how this correlates to complex cell phenotypes is a focus. Many genes and regulatory elements fall into each positive hit of each GWAS study, and the actual target gene(s) that causes disease may fall outside of the regions identified by GWAS studies. Follow-up projects to the Human Genome Project, such as the NIH-funded Encyclopedia of DNA Elements (ENCODE) and the Roadmap Epigenomics Project, have identified millions of putative regulatory elements across the human genome for many human cell types and tissues. These regulatory elements determine the gene expression patterns responsible for complex cell phenotypes including cell differentiation, tissue specificity, oncogenesis, immunomodulation, and disease. However, the function of these regulatory elements and their relationships to these phenotypes are largely unknown. Additionally, conventional screening tools for perturbing cellular processes, such as small molecules and RNA interference, cannot directly target genomic regulatory elements.
Conventional screening technologies include small molecule screens that inhibit protein function and RNA interference screens that block protein translation. Although successful in many cases, these screening technologies have also been plagued by confounding off-target effects. Furthermore, as described above, it has been discovered that gene regulatory elements play a critical role in determining cell phenotype, susceptibility to various diseases and disorders, and response to drug treatment. Conventional screening technologies are unable to directly probe the function of gene regulatory elements. There remains a need for the ability to target direct manipulation of epigenetic properties.